Craig Dees,1 James S. Foster,2 Shamila Ahamed,2 and Jay Wimalasena2 1*Risk Analysis Section, Health Sciences Research Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee; 2Department of Obstetrics and Gynecology, University of Tennessee Hospital, Knoxville, Tennessee
It has been suggested that dietary estrogens neutralize the effect of synthetic chemicals that mimic the effects of estrogen (i.e., xenoestrogens, environmental estrogens). Genistein, a dietary estrogen, inhibits the growth of breast cancer cells at high doses but additional studies have suggested that at low doses, genistein stimulates proliferation of breast cancer cells. Therefore, if dietary estrogens are estrogenic at low doses, one would predict that they stimulate estrogen-receptor positive breast cancer cells to enter the cell cycle. Genistein and the fungal toxin zearalenone were found to increase the activity of cyclin dependent kinase 2 (Cdk2) and cyclin D1 synthesis and stimulate the hyperphosphorylation of the retinoblastoma susceptibility gene product pRb105 in MCF-7 cells. The steroidal antiestrogen ICI 182,780 suppressed dietary estrogen-mediated activation of Cdk2. Dietary estrogens not only failed to suppress DDT-induced Cdk2 activity, but were found to slightly increase enzyme activity. Both zearalenone and genistein were found to stimulate the expression of a luciferase reporter gene under the control of an estrogen response element in MVLN cells. Our findings are consistent with a conclusion that dietary estrogens at low concentrations do not act as antiestrogens, but act like DDT and estradiol to stimulate human breast cancer cells to enter the cell cycle. -- Environ Health Perspect 105(Suppl 3):633-636 (1997)
Key words: antiestrogen, breast cancer, DDT, phytoestrogen, xenoestrogen
This work was funded by laboratory directed research and development funds, U.S. Department of Energy. Work performed at the University of Tennessee Medical Center was supported by a grant from the National Institutes of Health to J. Wimalasena.
"The submitted manuscript has been authored by the contractor of the U.S. Government under contract DE-AC05-96OR22464. Accordingly, the U.S. Government retains a nonexclusive, royalty-free license to publish or reproduce the published form of this contribution, or allow others to do so, for U.S. Goverment purposes."
Address correspondence to Dr. C. Dees, PhotoGen L.L.C., 7327 Oak Ridge Highway, Suite A, Knoxville, TN 37931. Telephone: (423) 539-9975. Fax: (423) 539-9654. E-mail:genase@aol.com
*Oak Ridge National Laboratory is managed by Lockheed Martin Energy Research Corporation for the U.S. Department of Energy under contract DE-AC05-96OR22464.
Abbreviations used: A/G, albumin-globulin; ATP, adenosine triphosphate; Cdk2,cyclin-dependent kinase 2; ER, estrogen receptor; FBS, fetal bovine serum; PBS, phosphate-buffered saline; pRb105, retinoblastoma susceptibility gene product; t0, time zero.
This paper was presented in part at the Workshop on Hormones, Hormone Metabolism, Environment, and Breast Cancer held 28-29 September 1995 in New Orleans, Louisiana. Manuscript received at EHP 6 June 1996; manuscript accepted 8 August 1996.
Last Update: April 10, 1997